Disease relevance of Akap12

• Our data suggest a role for the loss of SSeCKS/Gravin in the metastatic progression of human prostate cancer [1].
• SSeCKS/Gravin expression was detected in benign human prostatic lesions and well-differentiated carcinomas but not in undifferentiated lesions with Gleason sums > or =6 [1].
• In nude mice, SSeCKS reexpression slightly decreased primary-site tumor growth but severely decreased the formation of lung metastases [1].

High impact information on Akap12

• Conditioned media from SSeCKS-overexpressing astrocytes (SSeCKS-CM) blocked angiogenesis in vivo and in vitro [2].
• SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier [2].
• Furthermore, immunoreactivity to SSeCKS gradually increased during the BBB maturation period, and SSeCKS-expressing astrocytes closely interacted with zonula occludens (ZO)-1-expressing blood vessels in vivo [2].
• Here we report that src-suppressed C-kinase substrate (SSeCKS) decreases the expression of vascular endothelial growth factor (VEGF) through AP-1 reduction and stimulates expression of angiopoietin-1 (Ang-1), an antipermeability factor in astrocytes [2].
• Our data suggest that SSeCKS controls G(1)-->S progression by regulating the expression and localization of cyclin D1 [3].

Biological context of Akap12

• Two targets, Akap12 and Marcks, are downregulated in transformed cells and are known tumor suppressor genes [4].
• Short-term addition of phorbol ester resulted in a 5-fold increase in SSeCKS phosphorylation which was inhibited by bis-indolylmaleimide [5].
• Gene trap insertion reveals two open reading frames in the mouse SSeCKS gene: the form predominantly detected in the nervous system is suppressed by the insertion while the other, specific of the testis, remains expressed [6].
• Thus, we propose to expand SSeCKS scaffolding functions to include the ability to control actin-based cytoskeletal architecture, as well as mitogenic signal pathways [7].
• In the present study, we mapped the in vitro binding sites for CaM and cyclins on SSeCKS [8].

Anatomical context of Akap12

• Short-term addition of phorbol esters caused the movement of SSeCKS from plasma membrane sites to the perinucleus coincident with a loss of actin stress fibers [5].
• These data suggest that mitogen-induced, FAK-dependent tyrosine phosphorylation of SSeCKS modulates its binding to the actin-based cytoskeleton, suggesting a role for SSeCKS in mitogen-induced cytoskeletal reorganization [9].
• In this study, we report the generation, via gene trapping in embryonic stem cells of mice carrying an insertion in the mouse SSeCKS gene [6].
• Finally, we show that P1- but not P2-mRNA expression is abolished by the insertion and furthermore that mice homozygous for the mutation lack SSeCKS in all tissues except the male germ cells [6].
• Ectopic expression of SSeCKS caused loss of cytoplasmic F-actin fibers in the mouse endothelial cell line LEII [10].

Associations of Akap12 with chemical compounds

• Hence, we named this product SSeCKS (pronounced essex) for Src Suppressed C Kinase Substrate [5].
• Mitogen-induced, FAK-dependent tyrosine phosphorylation of the SSeCKS scaffolding protein [9].
• The relative phosphotyrosine level on SSeCKS was higher in actively dividing cells than in confluent cultures [9].
• We isolated cDNA of the mouse homologue of the src-suppressed C kinase substrate (SSeCKS) and analyzed the effects of lipopolysaccharide (LPS) injection on the tissue expression pattern of this protein [10].
• Because the constitutive overexpression of SSeCKS is toxic [Lin et al., 1995], we developed cell lines with tetracycline (tet)-regulated SSeCKS expression [7].

Physical interactions of Akap12

• This correlated with increased coprecipitation of SSeCKS with biotin-phalloidin-bound F-actin from FAK-/- compared to FAK+/+ cell lysates [9].
• The mitogenic regulatory activity of SSeCKS is likely manifested by its ability to bind key signalling proteins such as protein kinases C and A and calmodulin, and to control actin-based cytoskeletal architecture [11].

Enzymatic interactions of Akap12

• Purified FAK or Src enzyme failed to directly phosphorylate SSeCKS in vitro [9].

Regulatory relationships of Akap12

• However, extracellular signal-regulated kinase 2 activity was induced 5-10-fold by SSeCKS in the presence of active src [12].
• CONCLUSION: Our data provide further evidence that SSeCKS can suppress Src-induced oncogenesis by modulating gene expression downstream of Src kinase activity [13].

Other interactions of Akap12

• Src-suppressed C kinase substrate (SSeCKS), a potent tumor suppressor, plays a role in membrane-cytoskeletal remodeling to regulate mitogenesis, cell differentiation, and motility [14].
• Confocal microscopy analysis revealed cytoplasmic colocalization of cyclin D1 with SSeCKS [3].
• Bacterially expressed SSeCKS-CY bound cyclins D1 and E, whereas K-->S mutations within either CY motif ablated binding [3].
• SSeCKS expression did not affect: (a) the protein level, in vivo or in vitro kinase activity of ts72src; (b) the activity of jun NH2-terminal kinase; and (c) the level of mitogen-activated protein kinase (extracellular signal-regulated kinase 2) protein [12].
• Using a panel of ras-transformed or revertant Rat-6 cells that exhibit selective parameters of transformation, we show that down-regulation of SSeCKS correlates with anchorage-independent growth [12].

Analytical, diagnostic and therapeutic context of Akap12

• Immunofluorescence analysis showed SSeCKS present throughout the cytoplasm with enrichment in podosomes and at the cell edge [5].
• Similarly, bacterially expressed, unphosphorylated SSeCKS cosedimented with F-actin in ultracentrifugation assays [9].
• Northern blotting analysis showed that SSeCKS mRNA was expressed abundantly in the testis but at undetectable levels in other tissues of untreated control mice [10].
• Both in situ hybridization and immunohistochemical studies revealed that LPS administration conspicuously elevated expression of SSeCKS mRNA and protein in vascular endothelial cells of several organs [10].
• METHODS: We use cDNA microarrays and semi-quantitative RT-PCR analysis to identify changes in gene expression correlating with i) SSeCKS expression in the absence of v-Src activity, ii) activation of v-Src activity alone, and iii) SSeCKS re-expression in the presence of active v-Src [13].

References